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- Springer Journals
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- Copyright © 2011 by Hautmann et al; licensee BioMed Central Ltd.
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- Medicine & Public Health; Oncology; Radiotherapy
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- 1748-717X
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- 10.1186/1748-717X-6-89
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- 21806799
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Abstract
Hautmann et al. Radiation Oncology 2011, 6:89 http://www.ro-journal.com/content/6/1/89 RESEARCH Open Access Clostridium difficile-associated diarrhea in radiooncology: an underestimated problem for the feasibility of the radiooncological treatment? Matthias G Hautmann , Matthias Hipp and Oliver Kölbl Background and Purpose: Over the last years an increasing incidence of Clostridium difficile-associated diarrhea (CDAD) has been reported. Especially haematology-oncology patients are at risk of developing CDAD. The aim of this analysis is to determine the incidence of CDAD in radiooncological patients and to find out what relevance CDAD has for the feasibility of the radiooncological treatment, as well as to detect and describe risk factors. Patients and Methods: In a retrospective analysis from 2006 to 2010 34 hospitalized radiooncological patients could be identified having CDAD. The risk factors of these patients were registered, the incidence was calculated and the influence on the feasibility of the radiooncological therapy was evaluated. Induced arrangements for prophylaxis of CDAD were identified and have been correlated with the incidence. Results: The incidence of CDAD in our collective is 1,6%. Most of the patients suffering from a CDAD were treated for carcinoma in the head and neck area. Common risk factors were antibiotics, proton pump inhibitors, cytostatic agents and tube feeding. Beside a high rate of electrolyte imbalance and hypoproteinemia a decrease of general condition was frequent. 12/ 34 patients had a prolonged hospitalization, in 14/34 patients radiotherapy had to be interrupted due to CDAD. In 21 of 34 patients a concomitant chemotherapy was planned. 4/21 patients could receive all of the planned cycles and only 2/21 patients could receive all of the planned cycles in time. 4/34 patients died due to CDAD. In 4/34 patients an initially curative treatment concept has to be changed to a palliative concept. With intensified arrangements for prophylaxis the incidence of CDAD decreased from 4,0% in 2007 to 0,4% in 2010. Conclusion: The effect of CDAD on the feasibility of the radiotherapy and a concomitant chemotherapy is remarkable. The morbidity of patients is severe with a high lethality. Reducing of risk factors, an intense screening and the use of probiotics as prophylaxis can reduce the incidence of CDAD. Keywords: Clostridium difficile-associated diarrhea, Clostridium difficile, Diarrhea, Colitis, Radiotherapy, Radiation Therapy, Chemoradiation Background and Purpose toxin and can therefore cause diarrhea [3]. CD is the aetiological agent for most of the cases of pseudo mem- Clostridium difficile (CD) appears normally as a harm- less environmental gram positive anaerobic bacteria branous colitis. Over the last years an increasing inci- which becomes pathogen in several circumstances [1,2]. dence of Clostridium difficile-associated diarrhea Clostridium difficile can be isolated from the stool of up (CDAD) has been reported. Furthermore, more severe to five per cent of healthy adults. Some strains produce courses of the disease have been described because of new virulent strains [3-6]. Several risk factors for CDAD are known. Beside anti- * Correspondence: matthias.hautmann@klinik.uni-regensburg.de biotic intake, other drugs like immunosuppressant, Institutional address: Department of Radiotherapy, University of Regensburg, Regensburg, Germany © 2011 Hautmann et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hautmann et al. Radiation Oncology 2011, 6:89 Page 2 of 7 http://www.ro-journal.com/content/6/1/89 cytostatic agents and proton pump inhibitors (PPI) have could be identified developing CDAD during radioonco- been identified to trigger CDAD [5,7-10]. Also tube logical treatment. feeding, parenteral nutrition as well as a reduced general In a retrospective analysis from 2006 to 2010 34 hos- condition and compromised immune function have pitalized radiooncological patients could be identified been described as risk factors [1,2,11]. having CDAD. In that time 2150 patients were on the Especially haematology-oncology patients are at risk of radiooncological ward in total (484 in 2006, 398 in developing CDAD [12-15]. Those haematology-oncology 2007, 423 in 2008, 384 in 2009 and 461 in 2010). patients often have systemic diseases and in many cases Radiooncological inpatients were identified from CD receive high dosed chemotherapy. positive patients registered in the department for micro- Radiooncological patients are mostly suffering from biology and hygiene. Beside that, the enquiry was done localised tumour and receive radiotherapy alone or with by checking codification for final payment. All patients a moderate dosed concomitant chemotherapy compared had to have at least one stool sample being tested posi- to chemotherapy of haematology patients. Because of tive for CD toxin A or B. the mainly local therapy radiooncological patients have Until the year 2008 all inpatients with watery diarrhea higher local toxicity. Especially stomatitis, mucositis and of more than 24 hours and all patients with medical his- dysphagia are common in radiooncological patients and tory of antibiotic intake and non-watery diarrhea of might be relevant as risk factors. more than 48 hours were screened for CDAD. Beside In summary a lot of radiooncological patients have that all patients with any diarrhea of more than 72 several risk factors. Beside concomitant chemotherapy, hours were screened for CDAD. For all patients a stool the frequency of a treatment with PPI and antibiotics is sample was collected and screened for Clostridium diffi- estimated to be high on a radiooncological ward cile toxin A and B by enzyme immunoassay. [16-19]. Also tube feeding and parenteral nutrition is Since 2008 for all patients with any diarrhea longer common [20-22]. than 24 hours were screened for CD toxin A and B. In CDAD has a lethality of 0.5% to 2.0% and an increas- case of clinical suspicion of CDAD and negative findings ing morbidity [3,14]. A high morbidity and a negative forCDtoxin AorB,two more stool sampleswere influence on the treatment of the underlying disease screened by enzyme immunoassay. have been documented, especially for surgical patients Since 2009 for all patients a stool sample was cultured or patients on intensive care units [23,24]. A high num- for toxigenic CD additionally to the enzyme ber of acute renal failure, weight loss, electrolyte imbal- immunoassay. ance and hypoproteinemia have been described [5,23]. All patients with positive findings for CD toxin A or B The influence of CDAD for the treatment of oncologi- had clinical symptoms of CDAD. In our collective no cal patients is not well reviewed. Because of the existing asymptomatic carrier could be identified. data, multiple problems for the treatment of those In case of suspicion of a relapse of CDAD, beside patients can be assumed [25,26]. screening for CD toxin A and B, a sigmoidoscopy was Often inpatient stay is prolonged because of CDAD. performed and a stool sample was cultured for toxigenic The costs for the health care system are high. There are CD. data showing estimated additional costs between 5243 The risk factors of the patients were registered. Anti- US$ and 8570 US$ in Europe per patient with a primary biotics and cytostatic agents applicated up to four weeks episode of CDAD and over 13600 US$ for a case of prior to diagnosis of CDAD were assessed. Patients with recurrent CDAD [5,27]. a long time medication of immunosuppressive drugs or Referring to this data, there might be a negative influ- patients with a Leukopenia CTC grade IV were counted ence on the feasibility of a radiooncological treatment as immunosupressed. The influence on the feasibility of for patients suffering from a CDAD. the radiooncological therapy in terms of interruption or The aim of this analysis is to determine the incidence abandonment of the radiotherapy, change of therapy of CDAD in radiooncological patients and to find out concept and the effect on the feasibility of chemother- what relevance CDAD has for the feasibility of the apy were evaluated. radiooncological treatment, as well as to detect and Induced arrangements for prophylaxis of CDAD were describe risk factors. identified and have been correlated with the incidence. Patients and Methods Results The study was performed for patients of a department Patient’s characteristics of radiotherapy of a German university hospital. In- and The incidence of CDAD in our collective is 1,6% (34 of outpatients were looked up for CDAD. Only inpatients 2150 patients). Of the 34 patients having a CDAD, Hautmann et al. Radiation Oncology 2011, 6:89 Page 3 of 7 http://www.ro-journal.com/content/6/1/89 24 were male, 10 were female. The median age was 67 Performance Status (KPS) of the patients was 70% Years with a standard deviation of 10 Years (Range from (range from 40% to 100%). 46 to 85 years). Twenty patients out of 34 (59%) had an antibiotic Most patients suffered from a head and neck cancer treatment up to four weeks before developing diarrhea. or metastases in the head and neck area. The most common antibiotic being taken was Pipera- Treatment areas were in 21 cases the head and neck. 7 cillin/Combactam with 29% of all patients (10/34 patients were treated thoracically, 5 pelvic and one patients) and 50% of the patients having an antibiotic abdominal (Table 1). treatment (10/20). Beside Piperacillin/Combactam, The average treatment time was 41 days with a stan- Ciprofloxacin (24% of all patients (8/34), 40% of the dard deviation of 19 days (Range from 5 to 74 days). patients receiving antibiotics (8/20)) and Moxifloxacin The average time as inpatients was 36 days with a stan- (18% (6/34), 30% (6/20)) were frequently used. In 2006 dard deviation of 22 days (Range from 2 to 80 days). and 2007 Moxifloxacin was frequently given. 45% (5/11) of the patients with antibiotic treatment in that period Risk factors received Moxifloxacin. Since suspicions arose that Moxi- The following data in terms of risk factors were col- floxacin triggers CDAD, in an antibiotic stewardship lected: The median pre treatment Karnofsky Moxifloxacin wasn’t given in routine since 2008. Only one more patient since 2007 developed a CD infection after receiving Moxifloxacin. Table 1 Patient characteristics Beside antibiotics, PPI, cytostatic agents and tube feed- sex Underlying disease ing were common in radiooncological patients. 1 F Anaplastic thyroid carcinoma Of the 18 patients with nutrition via gastric tube, 14 2 M Squamous cell carcinoma of the head and neck (SCCHN) had tube feeding as the only food intake. There was no 3 F Thyroid metastasis of an renal cell carcinoma patient on parenteral nutrition as the only food intake 4 M SCCHN (Table 2). 5 F Cervical carcinoma 6 M SCCHN Treatment of CDAD 7 M Bronchial carcinoma with a simultaneous SCCHN For all patients with CDAD therapy with PPI, antibiotics 8 F SCCHN and cytostatic agents was paused or stopped if possible. 9 M Bronchial carcinoma In two patients no further antibiotic treatment for CD 10 M SCCHN was necessary. Since 2007 all patients were treated with 11 M SCCHN probiotics (Saccharomyces boulardii) until there were no 12 F SCCHN more clinical symptoms for two days. 13 M Bronchial carcinoma Following the guidelines and recommendations of the 14 M M. Hodgkin Robert Koch Institute patients were treated with metro- 15 M Bronchial carcinoma nidazole as the first line therapy to avoid vancomycin 16 M SCCHN resistant enterococci. According to the dysphagia of the 17 M Anal carcinoma patients metronidazole was given oral, via gastric tube 18 M Bronchial carcinoma or parenteral. 19 F Giant cell B-NHL with an abdominal bulk Patients with a severe diarrhea, with a KPS of less 20 M SCCHN than 60% or with more than two episodes of CDAD 21 F Rectal carcinoma were treated with oral vancomycin as first line therapy. 22 M SCCHN If the symptoms did not disappear within five days of 23 M SCCHN treatment with metronidazole the therapy was changed 24 M SCCHN to vancomycin. 4 Patients were treated with combina- 25 M Oesophageal carcinoma tion of parenteral metronidazole and enteral 26 M SCCHN vancomycin. 27 F SCCHN The average treatment time with antibiotics was 15 28 M SCCHN days (range from 5 to 83 days). 29 F Cervical carcinoma 30 M Pelvine bone metastasis of a rectal carcinoma Arrangements for prophylaxis 31 M Oesophageal carcinoma Since 2008 the arrangements for prophylaxis have been 32 F SCCHN intensified. Antibiotics and PPI were restricted in use. 33 M SCCHN Tube feeding and parenteral nutrition as the only food 34 M SCCHN intake was avoided. All patients with diarrhea Hautmann et al. Radiation Oncology 2011, 6:89 Page 4 of 7 http://www.ro-journal.com/content/6/1/89 Table 2 Risk Factors Age [years] KPS Antibiotic treatment PPI Cytostatic agents Tube feeding Parenteral nutrition Immuno-suppression 1 85 40% + + - + - - 2 51 60% - + + + - - 3 69 60% + + - - - - 4 71 60% + + - + - - 5 46 90% - - + - - - 6 53 70% - + + + + - 7 67 80% + + + - - - 8 70 70% - + + + - - 9 66 70% + + - - - - 10 63 60% + - + + + - 11 81 60% + - - - + - 12 82 70% + + + + - - 13 70 50% + + - - - - 14 46 80% - + + - + - 15 67 60% + + + - - + 16 60 80% - - + - - - 17 59 60% + + + - - - 18 64 60% + + + - - + 19 68 70% + + + - - + 20 52 70% - + + + - - 21 81 50% - + - - - - 22 56 80% - - + + - - 23 61 70% - + - + - - 24 71 90% - - + + - - 25 74 100% - - + - - - 26 64 50% - + - + - - 27 69 70% + + + + - + 28 70 70% + + - + - - 29 57 90% + + + - - - 30 60 50% + + + - - - 31 85 80% - + + + - - 32 73 60% + - - + - - 33 75 50% + + - + - + 34 63 70% + + + + - - continuing longer than 24 hours and clinical suspicion Patients with four or more risk factors received pro- of having CDAD were isolated prophylactically. biotic medication (Saccharomyces boulardii) during the Isolation implicates a single room with a separate radiooncological treatment. Those patients with one epi- bathroom. Gloves and special gowns were used by the sode of CDAD received probiotic medication for the staff dealing with the patients on the ward and the staff remaining radiooncological treatment. dealing with the patient at the linear accelerator. Addi- The chronological incidence of CDAD showed one tional hand hygiene with water and soap for all persons patient of 484 in 2006 (incidence 0,2%), 16 of 398 in exiting the isolation room was performed as well as for 2007 (4,0%), 11 of 423 in 2008 (2,6%), 4 of 384 in 2009 the staff dealing with the patient at the linear accelera- (1,0%) and 2 of 461 in 2010 (0,4%). tor. Surface disinfection was intensified with sodium- hypochloride. Complications of CDAD In consultation with the Department of medical The effect of CDAD on patient treatment showed 24 of Microbiology and Hygiene in an antibiotic stewardship 34 patients (73%) with an electrolyte imbalance. Of Moxifloxacin was not used in clinical routine since those patients 15/24 (63%) had an imbalance on two or 2008. more electrolytes. 4/34 patients needed intravenous Hautmann et al. Radiation Oncology 2011, 6:89 Page 5 of 7 http://www.ro-journal.com/content/6/1/89 substitution of the electrolytes, the others an oral or Chemoradiation is a standard treatment for different enteral substitution. carcinomas [17,29-31]. Many patients on radiooncologi- 27/34 patients (79%) developed a hypoproteinemia cal wards have at least this as a major risk factor with a need to treat it in 12/27 (43%) of these patients. [16,17,32]. Some of these patients develop Neutropenia Initially the median KPS of the patients was 70%. and are therefore immunocompromised [18,19]. After healing of the CDAD the median KPS was 50%. Several underlying diseases, mainly a reduced general 12/34 patients (35%) had a prolonged hospitalization condition and compromised immune function have of 7 days in average (range from two to 75 days). The been described as risk factors to develop CDAD [1,11]. Hospitalized radiooncological patients often need an patient with prolonged inhabitation of 75 days had to be treated on intensive care unit for most of the time. antibiotic or antimycotic medication during radiotherapy 12/34 patients had more than one episode of CDAD [21,22]. Beside those risk factors, the frequency of a during radiooncological treatment. All of these patients treatment with proton pump inhibitor is estimated to be had two episodes except one who had three. quiet high on radiooncological wards. Tube feeding and In 14/34 patients (42%) radiotherapy had to be inter- parenteral nutrition favour the onset of CDAD [3,33,34]. rupted because of CDAD. This interruption was four Especially head and neck cancer patients have a high days in average (range one to 27 days). rate of dysphagia [18]. Nearly all patients having a dys- Of those 14 patients with interruption of radiation the phagia of CTC grade II or higher requiring tube feeding average interruption was 10 days. In two patients radio- or parenteral nutrition [20,35]. Wolff et al. found a rate therapy could not be restarted. of dysphagia in head and neck tumour patients of 77% In 21 of the 34 patients a concomitant chemoradiation and a rate of Grad 3 leukopenia or higher of 11% [18]. was planned. For those 21 patients 89 cycles were In our collective all head and neck cancer patients but 3 planned altogether. 43% of the chemotherapy cycle (38 were addicted to tube feeding or parenteral nutrition of 89 cycles) could be applicated. (18/21). In 62% of the cases (13/21 patients) chemotherapy had There are data identifying underlying diseases of the to be stopped and could not be continued. Only 19% of gastrointestinal tract to be risk factors for CDAD [2,3]. the patients (4/21 patients) could receive all of the Whether abdominal or pelvine radiotherapy triggers planned cycles and only 10% of the patients (2/21 CDAD is not known. In our collective only one patient patients) could receive all of the planned cycles in time. received abdominal and five patients received pelvic In four patients an initially curative concept had to be radiotherapy. changed into a palliative treatment concept. A reduced Some data give evidence that haematological and general condition after the CDAD did not allow treating oncological patients are patients at risk for developing them in the initially planned concept. CDAD [12-14]. Most data exist for paediatric oncologi- Four patients (12%) died due to CDAD. One patient cal units and for bone marrow transplant units died in a septicaemia. Three patients did not recover [12,15,36,37]. In the reports on haematology-oncology adequate after the infection and died of complications. patients, that include patients undergoing radiotherapy, Two of the patients were treated with the combination no subgroup analysis was done for that collective of of metronidazole and vancomycin. One patient was trea- patients [13]. In summary there are no data about the ted with vancomycin and for the last patient treatment risk for radiooncological patients suffering from CDAD. was started with enteral metronidazole. This patient Ourdataconfirm theassumption that radiooncologi- refused further therapy of CDAD because of the cal patients are also patients at risk for an infection with advanced tumour stage and died of septicaemia. clostridium difficile. Several authors have shown a decrease in local control Discussion for different tumours due to unplanned interruptions of The incidence in our collective is with 1,6% high com- radiotherapy [38,39]. Bese et al. reported a decrease of pared to data in literature. Reichardt et al. describes an 1.4% per day of unplanned interruption for head and incidence of 0,1% for Europe and an incidence of 0,1% neck carcinomas. SCCHN are common in our collective to 2% for the USA [3]. Heinlen et al. could found an and often have an interruption of radiotherapy. incidence of 0,6% for the USA in the year 2003 [28]. 42% of the patients developing a CDAD need a pause Especially the patients with head and neck cancer have of the radiation. For those patients who have an inter- a high risk of developing CDAD. This might be due to a ruption of the radiotherapy, the average interruption multitude of risk factors. 19/34 of our patients were suf- time is ten days. A decrease of loco regional control of 10 to 12% for one week of interruption has been fering from a squamous cell carcinoma of the head and reported [38,40]. neck (SCCHN). Hautmann et al. Radiation Oncology 2011, 6:89 Page 6 of 7 http://www.ro-journal.com/content/6/1/89 Beside interruption of radiotherapy patients suffering With these arrangements and an intensive screening from CDAD have several additional factors decreasing for Clostridium difficile the rate of infections has the feasibility of the oncological treatment like weight declined from 16 cases in 2007 to 11 in 2008, 4 in 2009 loss, incomplete chemotherapy and a decrease of general and 2 in 2010. condition. Even though there is only little evidence in probiotics For bronchial carcinoma, studies have emphasized the reducing the rate of CDAD for patients at risk, we trea- importance of prolonged overall treatment time. One ted all patients with four or more risk factors frequently study suspected an increase of the risk of death of 2% [28,46-49]. even for a one day break [41]. A statistically significant decrease in overall survival for patients receiving a Conclusion radiochemotherapy for SCLC could be found [38]. The effect of CDAD on the feasibility of the radiother- Beside bronchial carcinoma and head and neck cancer, apy and a concomitant chemotherapy is remarkable. also for cervical carcinoma, anal cancer and several The morbidity of patients is severe with a high lethality. other carcinomas it has been reported that prolongation Reducing of risk factors, an intense screening and the of overall treatment time and interruption of radiother- use of probiotics as prophylaxis can reduce the inci- apy decreases the loco regional control [38]. For that dence of CDAD. reason, a CDAD is a serious problem for patients under- going radiotherapy. List of abbreviations Also the feasibility of chemotherapy concomitant to CD: Clostridium difficile; CDAD: Clostridium difficile:associated diarrhea; KPS: radiotherapy is important for loco regional control and Karnofsky Performance Status; PPI: Proton pump inhibitor; SCCHN: Squamous cell carcinoma of the head and neck overall survival [42]. Several authors suspect the cumu- lative dose of concomitant chemotherapy to be an Authors’ contributions important prognostic factor [43,44]. If you compare the MGH planned the design of the study, did identify the patients, register the patients’ data, correlate the data and drafted the manuscript. MH was feasibility of chemotherapy in our collective with data in participating in identification of patients data. OK participated in planning of literature, you can find a low cumulative dose for the the study and its coordination. All authors read and approved the final patients with CDAD [19]. manuscript. In our collective only 19% of the patients received the Competing interests complete chemotherapy dose. For example of the The authors declare that they have no competing interests. patients receiving Cisplatin only 3 of 13 patients Received: 5 April 2011 Accepted: 1 August 2011 received at least 200 mg/m Cisplatin. The poor feasibil- Published: 1 August 2011 ity of chemotherapy in our collective might decrease the loco regional control and overall survival for patients References suffering from a CDAD. 1. Vaishnavi C: Clinical spectrum & pathogenesis of Clostridium difficile associated diseases. Indian J Med Res 2010, 131:487-499. In summary with four patients dying due to CDAD, a 2. Hookman P, Barkin JS: Clostridium difficile associated infection, diarrhea change from a curative to a palliative concept in another and colitis. World J Gastroenterol 2009, 15:1554-1580. four patients, CDAD is a severe problem for radioonco- 3. 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Journal
Radiation Oncology – Springer Journals
Published: Aug 1, 2011